DESCRIPTION The epidemiological data showing NSAIDS reduce risk for AD demands further investigation at the animal model level. One major target of NSAIDs is Cox-2. Pasinetti and others have found that neuronal COX-2 is elevated in experimental neurodegeneration and in AD brain and that overexpression of Cox-2 potentiates Abeta-mediated oxidative stress in vitro. Based on this and other data, they propose to: Aim 1. Study the role of Cox-2 in neurodegeneration using experimental Abeta and kainic acid damage in transgenic mice with neuronal, human C0X-2 (NHC) overexpression and in COX-2 knockout mice. They hypothesize COX-2 overexpression will increase neurodegeneration. Aim 2. To identify the role of COX-2 in primary cultures of NHC transgenic and COX-2 KO mice in the response to Abeta and glutamate neurotoxicity evaluated by MTT and neuronal counts. This parallels aim 1. Aim 3. To identify mechanisms involved in COX-2-mediated potentiation of Abeta toxicity using organotypic hippocampal slice cultures derived from NHC transgenic and COX-2 KO mice. The hypothesis that COX-2 overexpression amplifies free radical mediated DCF fluorescence and lipid peroxidation will be tested. Aim 4. To study the role of COX-2 overexpression in bigenic NHC X APPsw (Hsiao mice) which are hypothesized to have accelerated neurodegeneration and cognitive impairment.